Prior immunity to an unrelated pathogen can lead to beneficial effects such as enhanced viral clearance or detrimental effects such as increased viral load or remarkably increased immunopathology occurring as a consequence of T-cell cross reactivity (XR). Initially described under highly controlled conditions using animal models infecting with human respiratory pathogens such as influenza A (lAV), vaccinia (W), and lymphocytic choriomeningitis (LCMV) viruses, examples of such XR T-cell responses have now been associated with enhanced pathology in humans infected with Epstein-Barr (EBV) (by us), lAV, dengue, and hepatitis C (HCV) viruses. The overall objective of this grant is to exploit our developed mouse models to determine under controlled conditions, not possible in human studies, how T-cell XR impacts T-cell selection and function leading to detrimental effects resulting in exacerbation of disease outcome during respiratory infections. Simultaneously we will use our developed human T-cell expertise during viral infections to translate our findings in mouse models to human disease, specifically examining the association between CDS T-cell XR and the severity of lAV infection. We have identified networks of cross-reactive CDS T-cells in both mice and humans, in human studies, we found that the frequency of lAV-Mlss-specific memory CDS responses XR: with EBV-BMLFI280 in HLA-A2+ patients directly correlated with the severity of acute infectious mononucleosis. We have also observed in 5 EBV-seronegative HLA-A2+ middle-aged adults a unique XR between Mi-specific T-cells and EBV lytic epitopes, BMLF1 and BR.LF1, raising the intriguing possibility that these may be protective. We will focus this proposal first on proof of principle animal models examining the role of t-cell XR in mediating detrimental effects during respiratory infections in lAV-inimune mice subsequently infected with LCMV (lAV+LCMV), category C and A human pathogens, respectively. This model leads to severe lung pathology very similar to that observed in lAV pandemics. Our work will focus on the role of XR memory CD4 and CDS T-cells in mediating detrimental effects, either induction of lung pathology or enhancing viral load (Aim 1&2). At the same time we will determine in translational studies if there is any evidence that this unique XR CDS T-cell network between lAV and EBV is associated with the severity of disease during acute lAV infection in patients when both viruses are present (Aim 3). The overall objective of this proposal is to determine how XR T-cells impact T-cell selection and function and influence disease outcome, for better or worse, as the host is exposed to acute respiratory infections such as lAV.